Human metapneumovirus (hMPV) is a member of the genus Metapneumovirus in the subfamily Pneumovirinae of the family Paramyxoviridae. HMPV was first identified in infants and children with acute respiratory tract infections in 2001 in The Netherlands. Soon after its discovery, hMPV was recognized as a globally prevalent pathogen. It is a major causative agent of acute respiratory tract disease in individuals of all ages, especially in infants, children, the elderly, and immunocompromised individuals. Epidemiological studies indicate that 5 to15% of all respiratory tract infections in infants and young children are caused by hMPV, a proportion second only to that of human respiratory syncytial virus (RSV). The clinical signs and symptoms associated with hMPV are similar to those of RSV, ranging from mild respiratory problems to severe coughs, bronchiolitis, and pneumonia. Currently, there are no therapeutics or vaccines available for hMPV. The only other member in the genus metapneumovirus is avian metapneumovirus (aMPV), which also is known as avian pneumovirus or Turkey Rhinotracheitis, is an economically important pathogen that causes acute respiratory disease in turkeys.
All viruses must cross the cell membrane to initiate infection. Paramyxoviruses enter host cells through the fusion of viral envelops with cellular membrane. Such fusion is mediated by viral glycoproteins that are located on the surface of virion envelope. For viruses in the Paramyxoviridae subfamily of the Paramyxoviridae family, membrane fusion requires both the attachment proteins (G, H, or HN) and the fusion (F) protein. Paramyxovirus F protein is a class I fusion protein, which is first synthesized as a precursor protein, F0, and subsequently cleaved into two disulfide-linked subunits, F1 and F2, by proteases in host cells. This cleavage generates a hydrophobic fusion peptide (FP), which is directly inserted into the membrane to initiate fusion. Paramyxovirus F proteins contain two conserved heptad repeat (HR) regions, the N-terminal heptad (HRA) and the C-terminal heptad (HRB), which are located downstream of the fusion peptide and upstream of the transmembrane (TM) domain, respectively. Upon triggering, the metastable pre-triggered F protein undergoes a series of dramatic and irreversible conformational changes. HRA and HRB are rearranged to form a highly stable six-helix bundle that brings two membranes together to initiate fusion.
Currently, the mechanism which triggers fusion so that it occurs at the right time and in the right place remain poorly understood. It is thought that binding of the attachment proteins to the cell surface receptor(s) induces conformational changes in F protein, which in turn triggers membrane fusion.
Membrane fusion of pneumoviruses is unique among the paramyxoviruses, in that fusion is accomplished by the F protein alone without help from the attachment glycoprotein. This attachment protein independent fusion activation has been well characterized in human respiratory syncytial virus (hRSV), bovine RSV (RSV), and ovine RSV. Recently, it was found that the F protein of hMPV, was able to induce fusion without the G protein. Recombinant hMPV lacking G protein was found to replicate efficiently in cell culture. Some hMPV strains require low pH, whereas fusion of all other paramyxoviruses occurs at neutral pH. In addition, fusion of hMPV requires trypsin.
F protein of hMPV alone is sufficient for induction of cell-cell fusion and viral entry indicating that hMPV F protein must possess dual functions, receptor binding and fusion promotion. It was found that integrin αvβ1 is a functional receptor for hMPV. This is based on the observations that (i) αvβ1 antibody inhibited hMPV infectivity; (ii) siRNA targeting αvβ1 integrin blocked hMPV infectivity; (iii) F proteins of all known hMPV strains contain a putative integrin-binding motif (329RGD331); and (iv) a point mutation (D331E) in RGD motif inhibited binding of F protein to αvβ1 integrin in host cells. In contrast, RGD is not essential for cell-cell fusion triggered by hMPV F protein. However, this conclusion is based on the observation that a single point mutation (D331E) in RGD motif in F protein did not significantly affect fusion activity and viral infectivity. Rather, heparin sulfate proteoglycans function as primary receptors for hMPV which is mediated by F, but not G protein. It was hypothesized that the interaction between integrins and hMPV occurs after the initial binding of hMPV F to heparan sulfate proteoglycans. This is consistent with the hypothesis that heparan sulfate serves as an adhesion factor for hMPV with subsequent integrin engagement being critical for entry. Nonetheless, molecular mechanisms underlying the interaction between hMPV F and integrin, and their roles in cell-cell fusion, viral binding, and hMPV life cycle have not been elucidated.
It would be beneficial to further elucidate the underlying mechanisms o hMPV and integrin interaction, and their roles in cell-cell fusion, viral binding, and hMPV life cycle. Also beneficial would be the development of hMPV vaccines